Transcript cd anti stress

WHAT IS EPIGENETICS?
In the early 1940s, C. H. Waddington
coined the term epigenetics to mean
“above or in addition to genetics”
“genome information that is superimposed on the DNA sequence”
How can identical twins have different
hair colors?
How do different adult stem cells know
their fate?
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Myoblasts can only form muscle cells
Keratinocytes only form skin cells
Hematopoetic cells only become blood cells
But all have identical DNA sequences.
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Modern definition is non-sequence dependent inheritance.
Epigenetic phenomena are reversible
Epigenetic phenomena are critical for the embryonic
development, aging, and the process of many diseases
including cancers.
A bridge that connects environmental factors to our genes and
bring the phenotype into being.
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EPIGENETIC MECHANISMS
RNA Interference
Gene Expression
Histone Modifications
DNA Methylation
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DNA METHYLATION
DNA methylation is a unique modification of DNA and the most
common epigenetic phenomenon in eukaryotic cells.
DNA methyltransferases catalyze the transfer of methyl group from
S-adenosylmethionine (AdoMet) to the carbon-5’ position of
cytosine in CpG dinucleotides.
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HISTONE MODIFICATION
When histones are tagged, or acetylated, chromatin is open and
genes are potentially active;
When histones are not chemically tagged, deacetylated, the
chromatin condenses and genes silenced.
Levels of acetylation of the core histones result from the steady
balance between HAT and HDAC.
Active
Inactive
HDAC
HAT
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Non coding RNAs
RNA which is not used for
making proteins (non-coding
RNA) can be cleaved and
used to inhibit protein-coding
RNAs
siRNAs, microRNAs (~22
Nucleotides; fine tune gene
Expression)
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WHAT IS CANCER?
 Carcinogenesis
is a complex and multistep
process that involves the accumulation of
successive transformational events driven by
genetic mutations and epigenetic alterations that
affect major cellular processes and pathways
such as proliferation, differentiation, invasion
and survival
 These alterations affect normal gene regulation
and impede normal cellular processes including
cell cycle, DNA repair, cell growth,
differentiation and apoptosis.
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Abnormal accumulation of abnormal cells with a loss
of control to grow and spread
Cell Proliferation
Homeostasis
Regulation of Cell Cycle:
Cell Cycle Check points
Cell Death
Control of Apoptosis
Cancer arises from both, epigenetic and genetic abnormalities, that cause
deregulated gene expression and function
Regulation by genetics involves a change in the DNA sequence, whereas
epigenetic regulation involves alteration in chromatin structure and
methylation of the promoter region
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The human body is prone to developing cancer, from a very
early stage of life, until the end of life
 The human genome has several built in tumour suppressor
genes, whose protein products suppress the formation of
tumours. It is important for these genes to continue expressing
their tumour suppressor proteins as long as the person lives
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To date, more than 600 genes, including tumor suppressor
genes, oncogenes, and cancer-associated viral genes, have
been reported to be regulated by epigenetic mechanisms. For
example, these genes include APC, ER, RAR, p15, p16, p73,
DAPK1, E-cathedrin, GSTP1, LKB1, MGMT, TIMP3, and
VHL
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EPIGENETICS AND CANCER
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There is evidence that epigenetic deregulation can be a
preliminary transforming event. Epigenetic changes such as
global DNA hypomethylation and promoter-specific
hypermethylation are commonly observed in early-stage
tumors. This suggests that epigenetic alterations are early
events in the loss of cellular homeostasis and may precede
genetic mutations and genomic instability
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Deregulated epigenetic mechanisms may initiate genetic
instability, resulting in the acquisition of genetic mutations
that inactivate tumor-suppressor genes and activate oncogenes
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The most frequent epigenetic changes are increased
methylation of CpG (phopshorylated cytosine-guanine)
islands within gene promoters and deacetylation or
methylation of histones
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DNA METHYLATION AND CANCER
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Robertson, Nature Reviews Genetics, Vol6, 597
PROGRESSIVE CHANGES IN PROMOTER METHYLATION AT CPG SITES
DURING CANCER INITIATION AND PROGRESSION
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THE POSSIBLE ROLE OF DNA METHYLATION IN CARCINOGENESIS
Mechanism
Initiation &
early
progression
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Mutation
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Epigenetic gatekeeper gene silencing
Activation of normally silenced allele by loss of imprinting
Activation of oncogene and chromosomal instability
Interrelationship with histone modifications
Inactivation of repair gene
Spontaneous deamination at methylcytosine residue
Cancer
progression
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Epigenetic plasticity
Spreading of aberrant methylation
Metastasis
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Epigenetic plasticity
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HISTONE MODIFICATIONS AND CANCER
Acetylation and methylation
of lysine-rich histone tails are
two major post-translational
modifications involved in the
regulation
of
chromatin
structure
and
gene
expression. Alteration of
histone modification profiles
causing TSG silencing is
associated to carcinogenesis
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Genetic Mutations in Epigenetic Modifiers in Cancer
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 Epigenetic
alterations are reversible, unlike genetic
ones and occur at the earliest steps of
carcinogenesis, placing epigenetic drugs at the
forefront of cancer therapy and represent
opportunities not only for therapeutic but also for
preventive interventions
 “Epi-drugs", which are drugs targeting epigenetic
mechanisms, show promise in cancer therapy.
Natural products modulating epigenetic mechanisms
constitute part of the hope offered by pharmacoepigenomics in cancer prevention and treatment
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PLANT-DERIVED ANTICANCER DRUGS WITH
EPIGENETIC ACTIVITIES
Plant-derived anticancer drugs with epigenetic
tumor inhibitory mechanisms are divided into
 major
 minor groups
based on the number of publications and the
variety of targeted cancers.
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Major plant-derived anticancer drugs as epigenetic
modulators
POLY-PHENOLS
Polyphenols are plant secondary metabolites consisting of one or more (poly-)
phenol unit(s). Their conjugated systems, and hence, electron delocalization
properties enable them to efficiently quench free radicals. Additionally,
phenols bear several hydroxyl groups making them excellent hydrogen bond
donors which bind with high affinity to proteins and nucleic acids.
Flavonoids are the largest and best characterized polyphenols and include the
flavonols, flavones, catechins, flavanones, anthocyanidins, and
isoflavonoids. Several polyphenolics mediate their anticancer activities by
modulating the acetylation pattern of crucial genes and inhibiting
hypermethylation of tumor suppressor genes, which is a landmark in cancer
development
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Anacardic acids are plant phenols
extracted from traditional medicinal
plants predominantly belonging to
the Anacardiaceae family and have
been shown to exhibit antitumor
and anti-oxidant activity. Anacardic
acid and analogues, such as
benzamide derivatives, act as
epigenetic modulators by inhibiting
the HATs, p300, PCAF, and TBP
interacting protein (TIP60) in
cervical, breast, kidney, and
prostate cancer cells and in
lymphoid and myeloid leukemia
cells
OH
O
OH
R
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Curcumin or diferuloylmethane is a naturally
occurring flavonoid derived from the rhizome of
Curcuma longa (Turmeric). Curcumin epigenetically
inhibits cancer through modulation of histone
acetylation by altering the activities of both, HATs and
HDACs. Curcumin induces HDAC1 and HDAC2 or
inhibits HAT activity leading to a decrease in global
and in H3 and H4 histone acetylation in prostate, liver,
brain, and lymphoid leukemia cancer cells
O
H3CO
HO
OH
OCH 3
OH
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ALKALOIDS
Alkaloids are naturally occurring compounds containing
basic nitrogen atoms.
CH
3
O
NH
N
CH3
H2N
Procainamide shows promising anticancer properties
particularly through epigenetic modulation of DNA
methylation. It inhibits DNMT activity in myeloid leukemia
cells and specifically DNMT1 in colon cancer cells. DNMT1’s
affinity to its two substrates, hemimethylated DNA and SAM,
was decreased by procainamide through partial competitive
inhibition. The inhibition of DNMT activity by procainamide
leads to decreased promoter methylation of several genes, thus,
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inducing their expression.
TERPENOIDS
Terpenes are hydrocarbons derived from fivecarbon isoprene
units they can be modified to terpenoids through addition of
oxygen atoms or skeletal rearrangements.
Parthenolide, a 15-carbon terpenoid (sesquiterpene lactone), is
commonly extracted from the European feverfew herb (Tanacetum
parthenium) that specifically depletes HDAC1 proteins. Parthenolide also
inhibits DNMT1 in lymphoid and myeloid leukemias
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Minor plant-derived anticancer drugs as epigenetic
modulators
Other plant-derived anticancer drugs have shown promise
as epigenetic modulators but were classified as minor
compounds as their epigenetic mechanisms are less
established than the previously described major ones
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Biochanin A and Daidzein from Glycine max (Soybean)
Caffeic Acid and Chlorogenic Acid from Coffea arabica (Coffee)
Catechin and Epicatechin from Uncaria rhynchophylla (Cat's claw
herb)
Thymoquinone from Nigella sativa (Black seed)
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Examples of Plant derived epigenetic modulators for cancer
treatment
Compound
Source
Molecular targets
Anti-caner properties
3,3′Diindolylmethane
Digestive product
of
indole-3carbinol found in
cruciferous
vegetables
inhibitory effect on decrease of proliferation
HDAC
activity
by and promotion of tumor
inducing
proteasome- cell death
mediated
downregulation of several
HDAC iso-enzymes
Butyrate and its
derivatives
generated during
gut
flora-mediated
fermentation of
dietary fibers
Inhibit HDAC activity, cell
cycle
arrest,
induce
DNA inhibition of proliferation,
demethylation
inflammation
and
oxidative
stress,
modulation
of
detoxification potential,
and
induction
of
differentiation
and
apoptotic cell death
Compound
Source
Molecular targets
Anti-caner
properties
Naturally occurring
flavonoid derived
from the rhizome of
Curcuma longa
decrease
DNA
methylation,
decreases
HAT
activities
and
histone acetylation or
reduces the expression of
several
HDAC
isoenzymes accompanied
by increased histone
acetylation
Anti-oxidant, antiangiogenic,
antiproliferative
and pro-apoptotic
activities
(−)polyphenol of green DNA demethylating
Epigallocatec tea
agent
by
inhibiting
hin-3-gallate
DNMT1 and to decrease
promoter methylation of
various TSGs leading to
gene reactivation
anti-oxidant,
anti-proliferative,
anti-invasive, antiangiogenic and
pro-apoptotic
effects
Curcumin
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Compound
Source
Molecular targets
Anti-caner
properties
Genistein and
daidzein
polyphenols found inhibit DNMT1 activity,
in soybean
decrease methylation of
promoter
methylation of TSGs,
induce
histone
acetylation by inhibiting
HDACs and activating
HATs
Inhibit
oxidative
stress,angiogenesis,
modulation of cell
cycle
regulation,
and induction of
apoptosis
Quercetin
polyphenol largely Decrease
DNMT Inhibit
present in the plant activity leading to p16 stress
kingdom
promoter demethylation
and gene reactivation
oxidative
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Compound
Source
Molecular targets
Anti-caner
properties
Resveratrol
polyphenol found
in grape and grape
products
such as red wine
reduces DNMT1
expression
and
methylation
of
RARβ and PTEN
genes
inhibition of cell
proliferation,
induction of antiangiogenic
response,
and
increased rate of
apoptosis
Sulforaphane
isothiocyanate
found
cruciferous
vegetables
HDACi increasing
in total and promoterspecific
histone
acetylation
in
cancer cells
Decreased
proliferation
induction
apoptosis
and
of
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PLANT EXTRACTS WITH ANTICANCER AND
EPIGENETIC ACTIVITES
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Polyphenols possess potent anti-oxidant and anticancer
properties. Recently, polyphenol rich plant extracts have
shown epigenetic activities in a variety of cancer types by
modulating promoter methylation of critical tumor genes.
Green tea rich polyphenol extract was found to decrease
CDX2 and p16 promoter methylation in colon and gastric
cancer cells, as well as in primary gastric carcinoma cells
 The Japanese rose (Rosa rugosa), allspice (Pimenta dioica)
and pineapple guava (Feijoa sellowiana) crude extracts were
shown to modulate histone acetylation in prostate cancer cells.
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Most of the major plant-derived compounds are in cancer
clinical trials, namely, curcumin, which entered Phase III.

Among the minor plant-derived compounds, lycopene and
thymoquinone are in cancer clinical trials

Many epidemiological studies and research data suggest that a
diet rich in fruit and vegetables may reduce cancer incidence
by mediating multiple biological activities and conferring the
ability to counteract cell signaling cascades and mechanisms
leading to genotoxic damage, redox imbalances and other
forms of stresses associated or leading to a deregulation of
cellular homeostasis
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CRITICAL ASSESSMENT
During decades, the best way to fight against cancer
was to destroy pathologically altered cells with
cytotoxic anti-neoplastic drugs, which is still the
standardized regimen for chemotherapy. However, it
is now considered that chemoprevention, the use of
natural dietary agents and/or synthetic compounds
in healthy individuals without signs of malignancy,
may represent a better chance to avoid the burden of
cancer by delaying, preventing, or even reversing
the development of tumor cells
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CONCLUSIONS
Many plant-derived compounds have been identified for
their anti-cancer properties with an emerging field
regarding the modulation of epigenetic events. Most
compounds
are
evaluated
regarding
histone
modifications (mainly acetylation) and DNA methylation
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FUTURE DIRECTIONS
We need to consider the long-term and eventually transgenerational
effects
of
sustained
preventive
interventions. Furthermore, there is the necessity to
identify biomarkers to monitor the efficiency of
preventive interventions by epigenetic modulators and
eventually to predict the need of such interventions,
which is going towards a personalized medical
approach.
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REFERENCE
SCHNEKENBURGER, M., M. DICATO AND M.
DIEDERICH. 2014. PLANT-DERIVED EPIGENETIC
MODULATORS
FOR
CANCER
TREATMENT
AND PREVENTION. BIOTECHNOLOGY ADVANCES,
32: 1123–1132.
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THANKS